The basic mechanisms of the actions and interactions of ethanol and cocaine on the heart, and the possible role of their metabolite ethylcocaine, are still poorly understood. Even less is known about the influence of chronic ethanol ingestion on these actions and interactions. The goal of this proposal is to investigate the effects of chronic ethanol ingestion on the acute in vitro cardia electrophysiologic and inotropic actions of ethanol and cocaine alone, or in combination, and of their metabolite ethylcocaine. The studies will be performed using rat litter-mates isocalorically pair-fed two different regimens of a liquid diet for 30 weeks; a control diet without ethanol, and an experimental diet containing ethanol. Sinoatrial preparations and papillary muscles will be isolated from the control and the experimental animals to perform parallel experiments. Standard intracellular microelectrode techniques will be used to study: (a) the actions of the drugs on sinus mode automaticity (preparations beating spontaneously) and atrial and ventricular membrane potentials (preparations driven at a constant rate), and (b) their possible antiarrhythmogenic actions. The inotropic actions will be studied in papillary muscles by measuring tension with a force transducer. Specific protocols will be utilized to study the effects of the drugs a) on preparations driven at a constant rate, and (b) on the force-interval relationship. Specific interventions will be employed to probe the mechanisms of the actions of ethanol, cocaine, and ethylcocaine under different inotropic states or during enhancement or inhibition of particular cellular processes. The data collected will provide important information on (a) the mechanisms of action of ethanol and cocaine as well as the role of their metabolite ethylcocaine in the actions of the two drugs used in combination; and (b) the effects of chronic ethanol ingestion on the acute actions of ethanol and cocaine.